Immunotherapy for early triple negative breast cancer: research agenda for the next decade

Breast cancer; Drug development; ImmunoeditingCàncer de mama; Desenvolupament de medicaments; ImmunoedicióCáncer de mama; Desarrollo de fármacos; InmunoediciónFor decades, the systemic treatment of localized triple negative breast cancer (TNBC) has exclusively relied on chemotherapy. Recent advancements, however, are rapidly reshaping the treatment algorithms for this disease. The addition of pembrolizumab to neoadjuvant chemotherapy has indeed shown to significantly improve event-free survival for stage II–III TNBC, leading to its establishment as new standard of care in this setting. This landmark advancement has however raised several important scientific questions. Indeed, we desperately need strategies to identify upfront patients deriving benefit from the addition of immunotherapy. Moreover, the best integration of pembrolizumab with further recent advancements (capecitabine, olaparib) is yet to be defined. Lastly, extensive efforts are needed to minimize the impact on patients of immune-related adverse events and financial toxicity. The next decade of clinical research will be key to overcome these challenges, and ultimately learn how to optimally integrate immunotherapy in the treatment landscape of TNBC.Supported by an American-Italian Cancer Foundation Post-Doctoral Research Fellowship

Nursing workload and staff allocation in an Italian hospital: a quality improvement initiative based on nursing care score

Aim: To develop, implement, and evaluate a Nursing Care Score (NCS) system, built into the electronic health record, to optimize nursing workload and staff allocation. Design: A quality improvement (QI) initiative with a pre- and post-implementation design was conducted by an interprofessional team in the 33-bed cardio-thoracic unit of a 72-bed hospital in Palermo, Italy. Methods: A seven-phase process was used to develop, implement, and evaluate the NCS, which lists 53 nursing work tasks, each assigned a score from 1.5 to 5.0. The nurse-to-patient ratio on all shifts was determined by the NCS. Nurse satisfaction with both the existing system and the NCS workload system was assessed. Descriptive statistics and McNemar's test were used to analyze the data. Results: At pre-implementation, 92.5% of nurses reported that the existing system was not effective, 87.5% reported it did not enable them to provide adequate nursing care, and 20.0% believed that workload was fairly distributed. At post-implementation, 75.0% of nurses reported that the NCS system was effective (p = 0.0348), 85.0% reported that the NCS system enabled them to provide adequate care, and 85.0% believed that workload was fairly distributed. An NCS score of 65 ± 5 was found to distribute workload most fairly. Conclusion: An automatic electronic operating system to generate a daily workload report based on the NCS was successfully implemented and evaluated. The NCS provided relevant information to guide nurse managers in defining nurse-to-patient ratio and determining staff allocation. Nurses were satisfied with the NCS system. The steps used to develop, implement, and evaluate the NCS system may be transferable to other units and other hospitals

The Size-Linewidth Relation and Signatures of Feedback from Quiescent to Active Star Forming Regions in the LMC

To investigate the effects of stellar feedback on the gravitational state of giant molecular clouds (GMCs), we study $^{12}$CO and $^{13}$CO ALMA maps of nine GMCs distributed throughout the Large Magellanic Cloud (LMC), the nearest star-forming galaxy to our own. We perform noise and resolution matching on the sample, working at a common resolution of 3.5 arcseconds (0.85 pc at the LMC distance of 50 kpc), and use the \textit{SCIMES} clustering algorithm to identify discrete substructure, or "clumps." We supplement these data with three tracers of recent star formation: $8\mu$m surface brightness, continuum-subtracted H$\alpha$ flux, and interstellar radiation field energy density inferred from dust emission. The $^{12}$CO clumps identified cover a range of 3.6 dex in luminosity-based mass and 2.4 dex in average $8\mu$m surface brightness, representative of the wide range of conditions of the interstellar medium in the LMC. Our observations suggest evidence for increased turbulence in these clouds. While the turbulent linewidths are correlated with clump surface density, in agreement with previous observations, we find even better correlation with the three star formation activity tracers considered, suggesting stellar energy injection plays a significant role in the dynamical state of the clumps. The excess linewidths we measure do not appear to result from opacity broadening. $^{12}$CO clumps are found to be typically less gravitationally bound than $^{13}$CO clumps, with some evidence of the kinetic-to-gravitational potential energy ratio increasing with star-formation tracers. Further multi-line analysis may better constrain the assumptions made in these calculations.Comment: 23 pages, 12 figures, accepted for publication in the Astrophysical Journa

Quinta evaluación de genotipos de espárrago en invernadero y respuesta a técnicas de envasado

El espárrago es una hortaliza perecedera, que en Argentina se requiere extender el período de oferta y optimizar su productividad y presentación, imple-mentando diferentes estrategias como la comercialización de turiones cortos y el empleo de bolsas y bandejas de IV Gama. A tal fin, se realizó un ensayo con el objetivo de evaluar el comportamiento (5º año), de los genotipos italianos Ítalo, Zeno, Eros y Ercole, versus UC-157, norteamericano, como testigo. Se estudiaron diferencias en t totales y comerciales, Nº turiones totales y comerciales y distribución de calibres y defectos encontrados (turiones espigados y cortos). Se obtuvieron 578015 turiones.ha-1 totales, siendo la producción comercial/cosecha: 59 kg.ha-1. En pos-cosecha, se evaluó la evolución del peso fresco y tres tipos de envasado: atados, bandejas y bolsas para turiones cortos. El híbrido Ítalo presentó mejor adaptación para primicia. Sobre la evolución productiva, se encontró que es posible adelantar el período de cosecha un mes comparado con la producción a campo. Además se recomienda cosechar diariamente el cultivo para evitar turiones espigados. En poscosecha se consideró la conveniencia del empleo de la técnica de IV Gama, mediante la utilización de bolsas o bandejas, para la optimización de la calidad del producto final y para extender la vida de anaquel. De esta forma se demostró la importancia de una adecuada planificación que incluye la elección criteriosa del híbrido y el acondicionamiento y presentación del producto final.Asparagus is a perishable vegetable that in Argentina requires its period of supply to be extended and the optimisation of its productivity and presentation, implementing different strategies such as the presentation of short spears (turions) and the use of bags and trays for Category IV products. To this end, the behaviour of the genotypes Ítalo, Zeno, Eros and Ercole, of Italian origin, versus UC-157, from the USA, as a control, was evaluated in the fifth year of productivity. Differences in the following characters were studied: total and commercial spear yield, number of total and commercial spears, calibre distribution and the proportion of defects observed (spiked and short spears). The following mean values were obtained: 578015 spears.ha-1, with a commercial production of 59 kg.ha-1. In postharvest, the evolution of fresh weight was evaluated, plus the influence of three types of packaging: tied bundles, trays and bags for short spears. The hybrid Ítalo demonstrated superior behaviour for primary production performance. Regarding production evolution, it was shown that it is possible to forward the harvest period by one month compared to field production. Additionally, daily harvesting is recommended in the glasshouse to avoid spiked spears. In postharvest the desirability of using bags and trays for Category IV was considered, in order to optimise the quality of the final product and to extend shelf-life. By these means, the importance of adequate planning before crop planting, including judicious choice of hybrid and the conditioning and presentation of the final product, was demonstrated.Fil: Giménez Azara C.. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Facultad de Ciencias Agrarias; ArgentinaFil: Castagnino A.M.. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Facultad de Ciencias Agrarias; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Agronomía; ArgentinaFil: Diaz, Karina Elizabeth. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Agronomía; ArgentinaFil: Tarantino, M.B.. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Agronomía; ArgentinaFil: Rogers, William John. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnolológico Mar del Plata. Instituto de Investigaciones en Biodiversidad y Biotecnología. Laboratorio de Biología Funcional y Biotecnología; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Agronomía; Argentin

The Morpho-kinematic Architecture of Super Star Clusters in the Center of NGC 253

The center of the nearby galaxy NGC 253 hosts a population of more than a dozen super star clusters (SSCs) that are still in the process of forming. The majority of the star formation of the burst is concentrated in these SSCs, and the starburst is powering a multiphase outflow from the galaxy. In this work, we measure the 350 GHz dust continuum emission toward the center of NGC 253 at 47 mas (0.8 pc) resolution using data from the Atacama Large Millimeter/submillimeter Array. We report the detection of 350 GHz (dust) continuum emission in the outflow for the first time, associated with the prominent South-West streamer. In this feature, the dust emission has a width of approximate to 8 pc, is located at the outer edge of the CO emission, and corresponds to a molecular gas mass of similar to(8-17)x10(6) M (circle dot). In the starburst nucleus, we measure the resolved radial profiles, sizes, and molecular gas masses of the SSCs. Compared to previous work at the somewhat lower spatial resolution, the SSCs here break apart into smaller substructures with radii 0.4-0.7 pc. In projection, the SSCs, dust, and dense molecular gas appear to be arranged as a thin, almost linear, structure roughly 155 pc in length. The morphology and kinematics of this structure can be well explained as gas following x (2) orbits at the center of a barred potential. We constrain the morpho-kinematic arrangement of the SSCs themselves, finding that an elliptical, angular-momentum-conserving ring is a good description of both the morphology and kinematics of the SSCs

Outflows from Super Star Clusters in the Central Starburst of NGC253

Young massive clusters play an important role in the evolution of their host galaxies, and feedback from the high-mass stars in these clusters can have profound effects on the surrounding interstellar medium. The nuclear starburst in the nearby galaxy NGC253 at a distance of 3.5 Mpc is a key laboratory in which to study star formation in an extreme environment. Previous high resolution (1.9 pc) dust continuum observations from ALMA discovered 14 compact, massive super star clusters (SSCs) still in formation. We present here ALMA data at 350 GHz with 28 milliarcsecond (0.5 pc) resolution. We detect blueshifted absorption and redshifted emission (P-Cygni profiles) towards three of these SSCs in multiple lines, including CS 7$-$6 and H$^{13}$CN 4$-$3, which represents direct evidence for previously unobserved outflows. The mass contained in these outflows is a significant fraction of the cluster gas masses, which suggests we are witnessing a short but important phase. Further evidence of this is the finding of a molecular shell around the only SSC visible at near-IR wavelengths. We model the P-Cygni line profiles to constrain the outflow geometry, finding that the outflows must be nearly spherical. Through a comparison of the outflow properties with predictions from simulations, we find that none of the available mechanisms completely explains the observations, although dust-reprocessed radiation pressure and O star stellar winds are the most likely candidates. The observed outflows will have a very substantial effect on the clusters' evolution and star formation efficiency.Comment: Accepted to Ap

Assessment of COVID-19-related olfactory dysfunction and its association with psychological, neuropsychiatric, and cognitive symptoms

Purpose of reviewTo provide a detailed overview of the assessment of COVID-19-related olfactory dysfunction and its association with psychological, neuropsychiatric, and cognitive symptoms.Recent findingsCOVID-19-related olfactory dysfunction can have a detrimental impact to the quality of life of patients. Prior to the COVID-19 pandemic, olfactory and taste disorders were a common but under-rated, under-researched and under-treated sensory loss. The pandemic has exacerbated the current unmet need for accessing good healthcare for patients living with olfactory disorders and other symptoms secondary to COVID-19. This review thus explores the associations that COVID-19 has with psychological, neuropsychiatric, and cognitive symptoms, and provide a framework and rationale for the assessment of patients presenting with COVID-19 olfactory dysfunction.SummaryAcute COVID-19 infection and long COVID is not solely a disease of the respiratory and vascular systems. These two conditions have strong associations with psychological, neuropsychiatric, and cognitive symptoms. A systematic approach with history taking and examination particularly with nasal endoscopy can determine the impact that this has on the patient. Specific olfactory disorder questionnaires can demonstrate the impact on quality of life, while psychophysical testing can objectively assess and monitor olfaction over time. The role of cross-sectional imaging is not yet described for COVID-19-related olfactory dysfunction. Management options are limited to conservative adjunctive measures, with some medical therapies described

Where do stars explode in the ISM? -- The distribution of dense gas around massive stars and supernova remnants in M33

Star formation in galaxies is regulated by turbulence, outflows, gas heating and cloud dispersal -- processes which depend sensitively on the properties of the interstellar medium (ISM) into which supernovae (SNe) explode. Unfortunately, direct measurements of ISM environments around SNe remain scarce, as SNe are rare and often distant. Here we demonstrate a new approach: mapping the ISM around the massive stars that are soon to explode. This provides a much larger census of explosion sites than possible with only SNe, and allows comparison with sensitive, high-resolution maps of the atomic and molecular gas from the Jansky VLA and ALMA. In the well-resolved Local Group spiral M33, we specifically observe the environments of red supergiants (RSGs, progenitors of Type II SNe), Wolf-Rayet stars (WRs, tracing stars $>$30 M$_{\odot}$, and possibly future stripped-envelope SNe), and supernova remnants (SNRs, locations where SNe have exploded). We find that massive stars evolve not only in dense, molecular-dominated gas (with younger stars in denser gas), but also a substantial fraction ($\sim$45\% of WRs; higher for RSGs) evolve in lower-density, atomic-gas-dominated, inter-cloud media. We show that these measurements are consistent with expectations from different stellar-age tracer maps, and can be useful for validating SN feedback models in numerical simulations of galaxies. Along with the discovery of a 20-pc diameter molecular gas cavity around a WR, these findings re-emphasize the importance of pre-SN/correlated-SN feedback evacuating the dense gas around massive stars before explosion, and the need for high-resolution (down to pc-scale) surveys of the multi-phase ISM in nearby galaxies.Comment: 34 pages, 14 figures. Submitted to ApJ. Comments welcome! The density distributions will be made publicly available after journal acceptance of manuscript. Please feel free to contact us in the meantime if you would like to use the

Trial of Dexamethasone for Chronic Subdural Hematoma

BACKGROUND: Chronic subdural hematoma is a common neurologic disorder that is especially prevalent among older people. The effect of dexamethasone on outcomes in patients with chronic subdural hematoma has not been well studied. METHODS: We conducted a multicenter, randomized trial in the United Kingdom that enrolled adult patients with symptomatic chronic subdural hematoma. The patients were assigned in a 1:1 ratio to receive a 2-week tapering course of oral dexamethasone, starting at 8 mg twice daily, or placebo. The decision to surgically evacuate the hematoma was made by the treating clinician. The primary outcome was a score of 0 to 3, representing a favorable outcome, on the modified Rankin scale at 6 months after randomization; scores range from 0 (no symptoms) to 6 (death). RESULTS: From August 2015 through November 2019, a total of 748 patients were included in the trial after randomization - 375 were assigned to the dexamethasone group and 373 to the placebo group. The mean age of the patients was 74 years, and 94% underwent surgery to evacuate their hematomas during the index admission; 60% in both groups had a score of 1 to 3 on the modified Rankin scale at admission. In a modified intention-to-treat analysis that excluded the patients who withdrew consent for participation in the trial or who were lost to follow-up, leaving a total of 680 patients, a favorable outcome was reported in 286 of 341 patients (83.9%) in the dexamethasone group and in 306 of 339 patients (90.3%) in the placebo group (difference, -6.4 percentage points [95% confidence interval, -11.4 to -1.4] in favor of the placebo group; P = 0.01). Among the patients with available data, repeat surgery for recurrence of the hematoma was performed in 6 of 349 patients (1.7%) in the dexamethasone group and in 25 of 350 patients (7.1%) in the placebo group. More adverse events occurred in the dexamethasone group than in the placebo group. CONCLUSIONS: Among adults with symptomatic chronic subdural hematoma, most of whom had undergone surgery to remove their hematomas during the index admission, treatment with dexamethasone resulted in fewer favorable outcomes and more adverse events than placebo at 6 months, but fewer repeat operations were performed in the dexamethasone group. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Dex-CSDH ISRCTN number, ISRCTN80782810.)

A randomised, double blind, placebo-controlled trial of a two-week course of dexamethasone for adult patients with a symptomatic Chronic Subdural Haematoma (Dex-CSDH trial)

BACKGROUND: Chronic subdural haematoma is a collection of ‘old blood’ and its breakdown products in the subdural space and predominantly affects older people. Surgical evacuation remains the mainstay in the management of symptomatic cases. OBJECTIVE: The Dex-CSDH (DEXamethasone in Chronic SubDural Haematoma) randomised trial investigated the clinical effectiveness and cost-effectiveness of dexamethasone in patients with a symptomatic chronic subdural haematoma. DESIGN: This was a parallel, superiority, multicentre, pragmatic, randomised controlled trial. Assigned treatment was administered in a double-blind fashion. Outcome assessors were also blinded to treatment allocation. SETTING: Neurosurgical units in the UK. PARTICIPANTS: Eligible participants included adults (aged ≥ 18 years) admitted to a neurosurgical unit with a symptomatic chronic subdural haematoma confirmed on cranial imaging. INTERVENTIONS: Participants were randomly assigned in a 1 : 1 allocation to a 2-week tapering course of dexamethasone or placebo alongside standard care. MAIN OUTCOMES MEASURES: The primary outcome was the Modified Rankin Scale score at 6 months dichotomised to a favourable (score of 0–3) or an unfavourable (score of 4–6) outcome. Secondary outcomes included the Modified Rankin Scale score at discharge and 3 months; number of chronic subdural haematoma-related surgical interventions undertaken during the index and subsequent admissions; Barthel Index and EuroQol 5-Dimension 5-Level utility index score reported at discharge, 3 months and 6 months; Glasgow Coma Scale score reported at discharge and 6 months; mortality at 30 days and 6 months; length of stay; discharge destination; and adverse events. An economic evaluation was also undertaken, during which the net monetary benefit was estimated at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year. RESULTS: A total of 748 patients were included after randomisation: 375 were assigned to dexamethasone and 373 were assigned to placebo. The mean age of the patients was 74 years and 94% underwent evacuation of their chronic subdural haematoma during the trial period. A total of 680 patients (91%) had 6-month primary outcome data available for analysis: 339 in the placebo arm and 341 in the dexamethasone arm. On a modified intention-to-treat analysis of the full study population, there was an absolute reduction in the proportion of favourable outcomes of 6.4% (95% confidence interval 11.4% to 1.4%; p = 0.01) in the dexamethasone arm compared with the control arm at 6 months. At 3 months, the between-group difference was also in favour of placebo (−8.2%, 95% confidence interval −13.3% to −3.1%). Serious adverse events occurred in 60 out of 375 (16.0%) in the dexamethasone arm and 24 out of 373 (6.4%) in the placebo arm. The net monetary benefit of dexamethasone compared with placebo was estimated to be –£97.19. CONCLUSIONS: This trial reports a higher rate of unfavourable outcomes at 6 months, and a higher rate of serious adverse events, in the dexamethasone arm than in the placebo arm. Dexamethasone was also not estimated to be cost-effective. Therefore, dexamethasone cannot be recommended for the treatment of chronic subdural haematoma in this population group